ABSTRACT Exercise is a powerful physiological stimulus contributing to disease prevention and intervention. The protective and preventive effects of exercise are well-documented for metabolic, neurodegenerative, and cardiovascular diseases, and certain cancers. While scientists acknowledge the extensive benefits of exercise, there is still insufficient understanding about the underlying mechanisms by which exercise prevents disease and improves health across diverse organ systems. The NIH Common Fund has developed a forward-looking funding mechanism ? six tethered RFA's tied to creating a research consortium, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) ? to create resources and critical information for exercise and health investigators well into the future. Two products of the MoTrPAC collective efforts will be a publically available data resource that will enhance and accelerate subsequent mechanistic research on diseases and conditions affected by physical activity; and a biorepository of clinical and animal model samples to be used in studying exercise biology. Based on prior collaborative efforts, our group believes that we are ideally positioned to propose a protocol that will respond directly to the RFA, while at the same time execute the large volume of tests to complete the ~450 people required at each site within the MoTrPAC consortium. To accomplish all of our Clinical Center goals, we have developed a consortium ? the North Carolina Clinical Site Consortium (NCCSC). The NCCSC consists of the experienced research teams Duke University School of Medicine; East Carolina University (ECU); and Wake Forest School of Medicine (WFSM). As described in the study plan, the NCCSC weighed a number of alternatives for training regimens, timing, and type of tissue sampling, sample sizes for the four obligated study groups, and other factors, while staying within budget constraints. The following Aims will maximize the value of the data and sample repositories; this will be accomplished with the enrollment of 540 individuals and finishing 450. Aim 1: To determine the response of molecular transducers to a single acute bout of either aerobic or resistance training. Aim 2: To determine the responses of molecular transducers to a chronic exercise training program of either aerobic or resistance training. Aim 3: To determine the responses of molecular transducers to a detraining period following either aerobic or resistance training.